The purpose of this project is to identify the determinants of non- insulin-dependent diabetes (NIDDM) and other chronic diseases in the Pima Indians, and elucidate their natural history. Genetic and environmental risk factors for NIDDM have been studied. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose tolerance, occupational and leisure-time physical activity and diabetes in relatives are assessed. The role of plasma lipoprotein concentrations in the development of NIDDM has been studied by long- term follow-up of nondiabetic persons in whom lipids had been fractionated. In women, HDL cholesterol was a significant protective factor, even when controlled for confounding factors including estimates of obesity, hyperglycemia and insulin resistance. The association of menstrual irregularity with diabetes was studied in Pima Indian women to extend previous findings of an association with nulligravidity, which had been postulated to be due to infertility. Among non-obese women, diabetes was approximately 4 times as frequent in those with menstrual irregularity, supporting the hypothesis that hyperandrogenism and hyperinsulinemia may underlie both disorders. An association was found between internal locus of control (a measure of one's perception that life events are under personal control) and physical activity among nondiabetic Pima Indians. As physical activity is negatively associated with diabetes in this and other populations, this finding suggests that psycho-social factors contribute to behaviors which affect risk of diabetes.